Higher prevalence of harbouring BCR::ABL1 in first-degree relatives of chronic myeloid leukaemia (CML) patients compared to normal population

Background The role of familial influence in chronic myeloid leukaemia (CML) occurrence is less defined. Previously, we conducted a study to determine the prevalence of harbouring BCR::ABL1 in our local adult normal population (designated as StudyN). We present our current study, which investigated the prevalence of harbouring BCR::ABL1 in the normal first-degree relatives of local CML patients (designated as StudyR). We compared and discussed the prevalence of StudyR and StudyN to assess the familial influence in CML occurrence. Methods StudyR was a cross-sectional study using convenience sampling, recruiting first-degree relatives of local CML patients aged ≥ 18 years old without a history of haematological tumour. Real-time quantitative polymerase chain reaction standardised at the International Scale (BCR::ABL1-qPCRIS) was performed according to standard laboratory practice and the manufacturer’s protocol. Results A total of 96 first-degree relatives from 41 families, with a mean age of 39 and a male-to-female ratio of 0.88, were enrolled and analysed. The median number of relatives per family was 2 (range 1 to 5). Among them, 18 (19%) were parents, 39 (41%) were siblings, and 39 (41%) were offspring of the CML patients. StudyR revealed that the prevalence of harbouring BCR::ABL1 in the first-degree relatives was 4% (4/96), which was higher than the prevalence in the local normal population from StudyN, 0.5% (1/190). All four positive relatives were Chinese, with three of them being female (p > 0.05). Their mean age was 39, compared to 45 in StudyN. The BCR::ABL1–qPCRIS levels ranged between 0.0017%IS and 0.0071%IS, similar to StudyN (0.0023%IS to 0.0032%IS) and another study (0.006%IS to 0.016%IS). Conclusion Our study showed that the prevalence of harbouring BCR::ABL1 in the first-degree relatives of known CML patients was higher than the prevalence observed in the normal population. This suggests that familial influence in CML occurrence might exist but could be surpassed by other more dominant influences, such as genetic dilutional effects and protective genetic factors. The gender and ethnic association were inconsistent with CML epidemiology, suggestive of a higher familial influence in female and Chinese. Further investigation into this topic is warranted, ideally through larger studies with longer follow-up periods. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-024-12102-2.

Supplementary Table 1 We used our previous criteria (1) to include or exclude the studies into this table.
• The exclusion criteria were: (1) No TWC or cytogenetics/PCR data, (2) CML variant presented with normal TWC and only thrombocytosis with Ph chromosome and/or BCR::ABL1 fusion gene positive(2) (this variant was previously thought to be Essential Thrombocythaemia), and (3) Post-allogenic haematopoietic stem cell transplantation (HSCT) (to eliminate potential treatment or immunomodulating effect from allogenic HSCT).
We also used our previous criteria (1) to determine the time point of CML CP diagnosis: • TWC > 15 × 10 9 /L in the presence of typical peripheral blood film (PBF) and bone marrow aspiration (BMA) features(2), along with the presence of Ph and/or BCR::ABL1(2).• If TWC ≤ 15 × 10 9 /L, the diagnosis required absolute basophilia (absolute basophil count ≥ 0.2×10 9 /L), typical PBF and BMA features, and Ph in ≥ 75% of the examined metaphases.• Once CML CP was diagnosed using above criteria, subsequent data was excluded even if the laboratory data did not meet the CP criteria mentioned above.
Supplementary Table 1 CML, chronic myeloid leukaemia; CP, chronic phase; F, female; Hb, haemoglobin; M, male; NR, not reported/done/available; Ph, Philadelphia chromosome; TWC, total white blood cell.a the study only reported Ph was detected in 3 metaphases.Assumed total of 20 metaphases were analysed.b result from Fluorescence In-Situ Hybridization (FISH).The sample source was indicated as peripheral blood (PB) or bone marrow (BM).C result was from BM that showed Ph in 4 of 20 metaphases.FISH was positive in 52% of the BM cells.d result from retrospective analysis of the patient's cord blood sample using nested genomic DNA-based PCR of which BCR::ABL1 fusion was identified in 2/4 replicates.The baby girl was diagnosed with CML CP at the age of 6 months.e from the first evidence of pre-clinical CML till diagnosis of CML CP (see text for criteria of CML CP).g group 1 indicates patients who had a history of cytotoxic therapy ± radiotherapy for hematopoietic or nonhematopoietic malignancies.group 2 indicates patients who had prior or concurrent hematopoietic or nonhematopoietic malignancies but did not receive cytotoxic therapy ± radiotherapy.group 3 indicates patients without prior or concurrent malignancies.h result was derived solely from cytogenetic result.43) -Language: Russia.Unable to find full article.Abstract in English stated "In one of the families, polycythemia vera (PV) was seen in twin brother and sister, in the other one, chronic myeloleukemia (CML) afflicted both daughter and mother, and in the two remaining families PV and CML afflicted two brothers and mother and daughter, respectively."4. Human leucocyte antigen (HLA) information was only available in one case report (37) and the result was conflictingthe two affected siblings have HLA-A3 (lower risk) and A11 (higher risk), respectively.

Study Group g Age (year) Gender TWC (x 10 9 /L) Hb (g/dL) Platelet (x 10 9 /L) Eosinophil (x 10 9 /L) Basophil (x 10 9 /L) %Ph in cytogenetic Duration (months) e
. Summary of the selected case reports on pre-clinical CML with available parameters of interest No.

Table 2 SupplementaryTable 2 .
(1).Search strategy and term: see Kuan JW et al(1).2.May not be a complete list because last search was July 2017.Subsequent studies were found based on web notifications.Prevalence of BCR::ABL1 M-BCR positivity in normal subjects/population , significant family history of breast, liver, lung, and stomach cancer.Note: 1.Primary search: all fields in PubMed on 28 th August 2023.Search term: (chronic myeloid leukaemia OR chronic myeloid leukemia OR chronic myelogenous leukaemia OR chronic myelogenous leukaemia OR CML) AND (familial OR hereditary OR inherited OR family OR relative).Secondary search: relevant references in selected studies from the primary search.2.Excluded familial cases with CML and other diseases and cases without evidence of Ph and/or BCR::ABL1.3.Bondare DK 1985( (34)udy includes relatives of known CML patients.bstudyon patients with peripheral blood cytoses but were not diagnosed as CML later.cassumedadult.Quoted 2 families recoded in Videbzek A (1947)(34). p PCR for BCR::ABL1 test (major transcript or assumed major transcript if did not specify in the report): + positive, -negative, 0 not done, ?unknown/NA.d1, underlying ANKRD26-related familial thrombocytopenia.d2